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Contact information Recent publications Curriculum vitae Laboratory of Molecular Biology |
Biography: Dr. Cheng obtained her Ph.D. from the University of California, San Francisco Medical Center. She received her postdoctoral training at the University Chicago and NIDDK. She joined NCI as a senior investigator in 1979 and was promoted to Section Chief in 1991. Dr. Cheng is a recipient of the NIH Merit Award for outstanding achievements and the Scientific Achievement Award from the Chinese Medical and Health Association.Research: The thyroid hormone, 3,5,3'-triiodo-L-thyronine (T3) is critically important in development, growth, differentiation and regulation of metabolic processes. In humans, its importance is exemplified by irreversible mental and growth retardation if congenital hypothyroidism is not recognized and treated. We are interested in understanding how this pluripotent hormone exerts its pleiotropic effect. Understanding the molecular mechanisms by which T3 mediates its biological effects will help us understand and manage better thyroid hormone related diseases, such as the genetic disease, thyroid hormone resistance syndrome.The biological activity of T3 is mediated by the thyroid hormone nuclear receptors (TRs). However, how TRs mediate the growth promoting effect of T3 is not known. Our recent studies indicate that the growth stimulatory effect of T3 is due to a shortening of G0/G1 phase accompanied by an increase in the S and G2/M phases of the cell cycle. These changes in cell cycle correlate with T3-induced increases in the mRNA and protein levels of two key regulators of the G1 progression, cyclins D1 and E, as well as that of cdk2. In addition, the kinase activities associated with cyclins D1 and E are activated up to 4-fold by T3. The T3-induced increases in the cdk kinase activities result in increased phosphorylation of the retinoblastoma protein (Rb) and the expression of E2F-1 protein to propel the entry of cells from the G1 to the S phase. These results show for the first time that the growth promoting effect of T3 is mediated, at least in part, by the cdk/Rb/E2F pathway. The functional link of TRs to Rb has important implications for the understanding of the biology of normal and cancer cells.TRs are T3-dependent transcription factors. However, the role of T3 in nuclear translocation and targeting of TRs to the regulatory sites in chromatin is unknown. We appended green fluorescent protein (GFP) to the TR subtype beta1 (TRbeta1) and used it to visualize the subcellular localization of TRbeta1 in living cells by laser-scanning confocal microscopy. In the presence of T3, most of the expressed GFP-TRbeta1 was found in the nucleus and excluded from the nucleolus. In the absence of T3, the GFP-TRbeta1 is evenly distributed between the nucleus and the cytoplasm in a subset of cells (~40%). In these cells, cytoplasmic GFP-TRbeta1 could be induced to enter the nucleus by T3. The T3-induced translocation is blocked when the nuclear localization signal in domain D is mutated. Furthermore, the inability of the mutant TR to translocate to the nucleus correlates with the loss of most of its transcriptional activity. Our study identified a novel regulatory role of T3 which is to modulate the nuclear entry fo TRs.We have previously shown that the transcriptional activity of TRbeta1 is modulated by the tumor suppressor p53. We examined whether TRbeta1 could affect the functions of p53. Mapping of the domains of p53 responsible for the interaction with TRbeta1 indicates that the regions involved reside in the DNA-binding domain and carboxy-terminus of p53. This physical interaction leads to the repression of p53-dependent transcriptional activation and inhibition of the expression of the p53-target genes, IbaxI and Igadd45I. These results further support the hypothesis that there is cross-talk between the signaling pathways of these two transcriptional factors.Our collaborators are Qimin Zhan, M. D., Laboratory of Molecular Pharmacology, NCI, Gordon L. Hager, Laboratory of Receptor Biology and Gene Expression, NCI, and John A. Hanover, Laboratory of Cellular Biochemistry and Biology, NIDDK.Recent Publications: |
Contact Information: Laboratory of Molecular Biology,NCI, NIHBuilding 37, Room 2D2437 CONVENT DR MSC 4255BETHESDA MD 20892-4255Phone: 301-496-4280Fax:301-480-9676Email: sycheng@helix.nih.gov
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